What the pulmonary specialist should know about the new inhalation therapies

Limitations of aerosol therapy

Not all inhalation devices are appropriate for all patients. This is because of differences in the way the devices perform and the need to master specific inhalation techniques, which require varying levels of cognitive ability depending on the device. Reviews of randomised controlled trials comparing different inhalers have concluded that they are all equivalent [6, 7]. However, patients in randomised controlled trials receive more inhaler-technique training and counselling on the importance of adherence than patients who are seen as part of routine clinical practice. For this reason, the Global Initiative for Asthma (GINA) and the British Thoracic Society (BTS) guidelines recommend that inhaler technique and the degree of adherence with dose regimens should be assessed before changing a patient's inhalation therapy [1–3].

Based on a real-life setting, it has been reported that 76% of patients using a pMDI and 49–54% of those using a BA-pMDI make at least one error when using their inhaler [10]. In addition, between 4 and 94% of patients using a DPI do not use it correctly and 25% have never received inhaler-technique training [11]. Failure to exhale to functional residual capacity before inhaling through their DPI device and failure to use a forceful, deep inhalation were two of the most common problems with DPIs [11]. With pMDIs, the most common problems were lack of actuation–inhalation coordination and stopping inhalation due to the cold freon effect [12]. Despite these errors, 50, 66 and 70–80% of general practitioners report that their patients inhale the right dose when they use a pMDI, BA-pMDI and a DPI, respectively [10].

When patients inhale a short-acting bronchodilator, they inhale another dose if they do not obtain a sufficient response from the first dose. As a result of this, they can overcome poor technique and potentially poor disease control by increasing their dose. Patients do not get this feedback from other inhaled therapies. For those drugs, it is important that patients use their device in an optimal manner and this often requires a specific and relatively complex inhalation manoeuvre that is tailored to the patient's needs and preferences [8].

Particle- and patient-related factors that influence aerosol deposition

Table 1 provides the definitions of terms commonly used to describe an aerosol. These terms are derived from in vitro measurements of particle-related characteristics and include dose and aerodynamic diameter. In terms of dose, physicians should be particularly aware that some countries label the inhaler with the nominal dose (which is the dose that is metered), while others use the emitted dose (which is the dose that comes out of the actuator and is available for inhalation at the mouth). For example, beclomethasone pMDI (hydrofluoroalkane (HFA) formulation, QVAR® (see Appendix for all product/drug manufacturer details)) is labelled as 100 μg (the nominal dose) in Europe and as 80 μg (the emitted dose) in the USA. Although these two references to dose are not the same, the dose that the patient receives is the same.

Drug delivery via the respiratory tract is more complex than oral therapy. Successful therapy requires a delivery system that generates drug particles of an appropriate size, such that they penetrate beyond the oropharynx and larynx and deposit in the lungs [13]. Aerodynamic diameter is generally thought to be the most important particle-related factor that affects aerosol deposition. Figure 1 shows the relationship between aerodynamic diameter and lung deposition [14]. Upon entering the oral cavity, particles will deposit by impaction, sedimentation and Brownian motion depending on their size. Particles >5 μm are most likely to deposit by impaction in the oropharynx and be swallowed [13]. This is partially the result of the inertia associated with the particle's mass, which reduces its ability to follow the airstream when it changes direction toward the lower airways. It is important to minimise corticosteroid deposition in the oropharynx because it can give rise to local side-effects, such as hoarseness and oral candidiasis with ICS [15].

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Figure 1–

The International Commission on Radiological Protection model showing the relationship between aerodynamic diameter and lung deposition. Data from [14].

Figure 1 also shows that particles that are <5 μm have the greatest potential for deposition in the lungs. The proportion of particles within an aerosol that are <5 μm is often referred to as the fine-particle fraction (FPF), or the fine-particle dose (FPD) if expressed in absolute mass of drug in particles <5 μm (table 1). Aerosols with high FPFs have a high probability of penetrating beyond the upper airways and depositing in the lungs. Thus, it is not surprising that current devices generate aerosols with a significant proportion of their particles in the 1–5 μm range. The optimal particle size range for aerosols delivered to children is not known. It is likely that it is smaller than the optimal size range for adults, due to narrower airway diameters and higher intraluminal flows.

Figure 1 shows that particles of 4–5 μm deposit primarily in the bronchial/conducting airways, whereas smaller particles remain in the airstream and are carried into the peripheral airways and the alveolar region. In the periphery of the lung, airflow rate is reduced and particles deposit predominantly by sedimentation, with gravity causing them to “rain out” and deposit. Most particles of 0.1–1 μm diffuse by Brownian motion and deposit when they collide with the airway wall. The longer the residence time in the smaller, peripheral airways, the greater the deposition from sedimentation and Brownian motion processes [16]. It is recommended that patients hold their breath after inhalation of an aerosolised medication because the breath-hold increases the residence time and this enhances deposition in the peripheral airways. Inhaled particles that do not deposit are exhaled [13].

Important patient-related factors include the morphology of the oropharynx and larynx and the patient's inspiratory volume and flow rate. The patient's inspiratory flow rate generally determines the velocity of the airborne particle and this, in turn, also affects the probability of its impaction in the oropharynx and larynx [17]. To minimise deposition in the upper airways and enhance delivery of the drug to the lungs when using a pMDI with or without a spacer, or a BA-pMDI, patients should inhale slowly. “Slowly” translates into inhaling fully over 2–3 s in a child and 4–5 s in an adult after a deep exhalation. This ensures that flows are ∼30 L·min⁻¹, which is the ideal flow when using a pMDI [18]. With DPIs, the patient has to inhale as deeply and as hard as they can to overcome the internal resistance to flow and generate the aerosol for inhalation. DPIs also require turbulent energy to de-aggregate their formulations and produce a FPD during the inhalation manoeuvre. The greater the energy imparted by the patient's inspiratory flow rate, the more effective the particle de-aggregation.

Lung disease and deposition

The degree of lung disease at the time of inhalation significantly influences the pattern of drug deposition within the lungs. Several studies have shown that central airway deposition is enhanced as mucus plugging, turbulent airflow and airway obstruction increase [19–23]. This means that in the face of severe lung disease, little or no drug may deposit in the lung periphery. This may not be clinically important for bronchodilators, but could be important for corticosteroids.

Drug receptors

Receptors for inhaled bronchodilators are distributed throughout the lungs [24, 25], but they have their greatest effect on receptors in the smooth muscle located in the conducting airways. By targeting these receptors, bronchodilators open up (dilate) the larger airways.

Corticosteroid receptors are also present throughout the airways [26] and inflammation has been shown to exist in all regions of the lungs in asthma [26] and COPD [27]. For these reasons, uniform distribution of an ICS throughout the airways, following inhalation, may be preferable. Further studies are needed to confirm this before recommendations can be made. Furthermore, there is doubt about the effectiveness, or role, of ICS in COPD [28], as reflected in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [2].

Nasal versus oral inhalation

The nose is a more effective filter than the mouth. Thus, inhalation through the mouth is the preferred route for aerosol delivery to the lungs. This is a potential issue when treating infants and toddlers. For example, when children are treated with nebulisers, or pMDIs with spacers or holding chambers, they frequently breathe through their noses using a facemask. While absolute efficiency in terms of lung dose is low during nose breathing, compared to mouth breathing [29], the total inhaled dose per kg of body weight is relatively higher in nose-breathing children compared with older patients using mouthpieces. Therefore, the dose to the lungs per kg body weight in nose-breathing infants is probably similar to that achieved by mouth-breathing adults [29].

Patient behaviour and deposition

For inhaled therapy to be effective, the patient must use a device effectively and adhere to a regular treatment regimen [8]. Adherence to treatment regimens is known to be frequently poor in all therapeutic areas and is probably not significantly worse with inhaled as compared with oral therapy. However, even if a patient is fully adherent with a treatment regimen, inhaled therapy may be ineffective if poor inhalation technique limits the amount of drug available for lung deposition. Studies have shown that a very high proportion of patients do not have the competence to use their device effectively, either because they have never been shown or because they have forgotten what they were taught [8, 30]. This is a particular problem in the elderly, but it does affect all age groups. Furthermore, many patients soon forget the correct technique that they have been trained to use [31]. In addition, many of those who are able to demonstrate a good technique in the clinic will contrive to use the device ineffectively in routine use. The most common example of contrivance is spacer disuse (e.g. patient's failure to use a spacer at home).

Data regarding the impact of education on regimen adherence is at best mixed, and it is very difficult to influence this aspect of patient behaviour. Having a good rapport with the patient has been shown to improve regimen adherence after a consultation, but this may be as transient as 1 week [31]. Patients may be more adherent with an inhaler that combines two drugs (i.e. LABA and ICS) in the same dose, compared with using two separate inhalers [32]. Although this may simplify the regimen, the effect is far from universal. While education per se probably does not have a significant impact on regimen adherence, patient feedback in terms of regimen adherence and automated reminders appear to influence this aspect of behaviour and are likely to become more frequently employed in clinical practice in the future [33].

Healthcare providers have a particular duty to ensure that patients are able to use their inhalers effectively [8]. Physicians must ensure that a suitable device is prescribed, that the patient is competent in the use of it and that the patient understands that little or no drug may reach the lungs if the device is not used according to the specified instructions. Competence and contrivance are amenable to educational intervention, though it is important to review these issues with the patient on a regular basis. Once a patient is familiar and stabilised on one type of inhaler, they should not be switched to new devices without their involvement and without follow-up education on how to use the device properly.

Choice of delivery device

The choice of device for a particular drug is determined by the devices that are available for that drug and whether the patient can and will use it effectively. Table 2 provides a summary of the devices that are currently available for delivery of the most commonly prescribed brand-name drugs, broken down according to pMDIs, BA-pMDIs, nebulisers, soft mist inhalers and DPIs. A pMDI requires good actuation–inhalation coordination for optimal lung deposition, whereas a DPI requires sufficient inspiratory flow. Table 3 provides information for choosing the right aerosol delivery device for patients with good versus poor actuation–inhalation coordination and sufficient inspiratory flow [34]. Patients with poor actuation–inhalation coordination include children and elderly patients. Where possible, patients should use one type of device for all of their inhaled therapies [1, 3]. However, this is not always possible. In the USA, there is no salbutamol DPI; patients may therefore have to use both a pMDI for their β₂-adrenergic agonist and a DPI for their other prescribed medications. Although previous publications have provided general inhalation technique recommendations for inhalers [7, 35], table 4 provides more detailed instructions on how to use pMDIs, BA-pMDIs, pMDIs with spacers, DPIs, nebulisers and soft mist inhalers. The major advantages and disadvantages of pMDIs with and without spacers, BA-pMDIs, nebulisers and DPIs are summarised in table 5 [9].

Regulation of delivery devices

In Europe, aerosol devices are regulated by the European Medicines Agency (EMA; www.ema.europa.eu). In the USA, the regulatory agency is the Food and Drug Administration (www.fda.gov).

Recommendations

Prescribers should:

1) Know the types of devices that are available to deliver specific drugs and classes of drugs (table 2).

2) Appreciate the advantages and disadvantages of each device (table 5).

3) Choose devices that the patient can and will use effectively (table 3).

4) Choose devices that have been approved by the appropriate authorities (table 2).

5) Train patients about the correct inhalation manoeuvre that is appropriate for the device being prescribed (table 4).

6) Check the patient's inhaler technique regularly.

7) Review the patient’s adherence to treatment at each visit.

8) Not switch to a new device without the patient's involvement and without follow-up education on how to use the device properly.

Pressurised metered-dose inhalers

Breath-actuated pressurised metered-dose inhalers

BA-pMDIs that are currently available are the Autohaler® and Easi-Breathe®. They were developed to overcome the commonly encountered problem of poor actuation–inhalation coordination with standard pMDIs [45]. The Autohaler® automatically actuates at inspiratory flow rates of ∼30 L·min⁻¹ and the Easi-Breathe® actuates at 20 L·min⁻¹. In one study, <5% of patients were unable to achieve the threshold inspiratory flow rate required for actuation of the Autohaler® and there were fewer errors [46], compared with using conventional pMDIs [10]. As shown in table 2, salbutamol and beclomethasone are available as BA-pMDIs in Europe. In the USA, only pirbuterol is available. For patients with poor actuation–inhalation coordination, BA-pMDIs may improve lung deposition, compared with pMDIs alone [45].

Spacers and valved holding chambers

Table 6 lists the most commonly used spacers. Spacers are accessory devices to be used with pMDIs. They can be simple extension devices that increase the distance between the pMDI and oropharynx, thereby reducing orophayngeal deposition, or they can be more elaborate. Spacers that incorporate a one-way valve are VHCs. They allow patients to inhale a static cloud. VHCs overcome the issue of coordinating actuation with inhalation, and they increase pulmonary deposition in those subjects who do not have optimal coordination when actuating a pMDI [47–50]. Spacers and VHCs should not be used with BA-pMDIs.

Due to the reduced impaction in the oropharynx, spacers and VHCs are recommended for use with ICSs. Impaction in the oropharynx is also reduced by using the QVAR® HFA-pMDI (without a spacer) [38]. Nevertheless, since some oropharyngeal deposition may still occur, patients are advised to rinse their mouths out after inhaling an ICS with any of these devices. Changing the spacer in effect represents a change in the delivery system. With a change in spacer device, regular monitoring and titration of the ICS dose to the lowest effective dose is advised.

Although the shape and volume of spacers can vary greatly, they are generally grouped into two categories: 1) small volume (130–300 mL) and 2) large volume (600–800 mL). Some spacers incorporate a whistle that makes a sound if inspiratory flow is too fast. Training subjects to ensure that the whistle does not sound assists with developing an optimal inhalation technique. Some spacers incorporate a reverse-flow design to enhance small particle delivery to the patient. In these spacers, the flow of aerosolised medication is directed away from the patient's mouth upon actuation and is then directed back towards the mouth during inhalation.

Some pMDIs are licensed with a specific spacer. For example, HFA Seretide® is licensed with the Volumatic® or Aerochamber®. Clenil® is licensed with the Volumatic® in the UK and with the Aerochamber® in the rest of Europe. QVAR® HFA and Alvesco® are licensed for use with the Aerochamber®.

A major disadvantage to spacers is that they are generally more bulky and less portable than a pMDI, and this often results in patients using the pMDI alone. Spacers also reduce the dose output from a pMDI to a variable extent. An additional source of variability in drug delivery with spacers is due to accumulation of an electrostatic charge on the plastic walls. Laboratory studies indicate that this electrostatic charge reduces spacer performance, such that the aerosol dose available for inhalation is reduced. This effect is most marked in newly purchased devices. The effect of electrostatic charge on the clinical outcome of an aerosolised medication is less clear and may affect some formulations more than others [51].

A number of “non-static” spacers have been developed. At present, there is a gradual country-by-country transition to the use of the Aerochamber®, which is made of a non-static plastic material. Another option is the Vortex®, which has an extremely thin metal layer on the inner surface of a plastic spacer that reduces static charge. The non-static metal Nebuchamber® is currently off the market.

Because spacers are generally used for many months, they require periodic cleaning to prevent deterioration in the function of the valve and for hygienic reasons [52, 53]. The general advice for both newly purchased and previously used devices is to clean them by washing them with a low concentration of dishwashing liquid and allowing them to drip dry [54]. In this way, the plastic is coated with detergent, which reduces the electrostatic charge, decreases drug losses on spacer walls and promotes lung deposition [55].

The PILs of the different spacers are not consistent in terms of how often a spacer should be cleaned. Recommendations range in general from once a week to once a month. One study suggests that the effect of the detergent coating on electrostatic charge diminishes within 1 week [56]. It is not clear if this applies to all devices, so the recommendation is to follow the guidelines for cleaning found in the PIL for individual spacers. There is no consensus on whether spacers should be rinsed after cleaning with dishwashing liquid. Therefore, it is important to follow the recommendation found in the PIL for each spacer in terms of whether to rinse after washing or not.

Only one dose should be actuated into the spacer prior to each inhalation because multiple inhalations increase drug losses within the spacer as a result of increased turbulence [57]. Furthermore, the dose should be inhaled immediately after it is introduced into the spacer. Time delays reduce the emitted dose because particles have more time to deposit within the spacer [57].

Dry powder inhalers

DPIs that are currently available are small and portable, and are breath-actuated, so patients do not have to coordinate actuation with inhalation. There are two basic types: 1) multi-dose DPIs, which contain many doses; and 2) single-dose capsule DPIs. There are also two versions of the multi-dose DPI: 1) those containing a bulk formulation in a reservoir, which is metered by the patient during use; and 2) pre-metered factory dispensed doses packaged inside blisters within the device. Table 2 shows that most DPIs are of the reservoir type.

All DPIs require the patient to prepare a dose prior to inhalation, as described in the PIL. Patients who do not perform these procedures correctly may receive no dose, irrespective of the inhalation manoeuvre they subsequently adopt. This type of critical error occurs frequently [58]. Some studies suggest that some patients have more problems using single-dose DPIs than multi-dose devices [59, 60].

Patients should be instructed to exhale into the room to functional residual capacity before inhaling through their DPI device. They should not exhale into the device, as that will result in blowing the dose out of the device. Failure to perform the proper exhalation manoeuvre before inhalation is the most common mistake made by DPI users [11]. Studies have also shown that dose emission is reduced when the DPI is exposed to extremely low and high temperature and humidity [61]. Therefore, DPIs should be stored in a cool dry place.

To ensure good powder flow during manufacture and consistency during dose metering, all DPIs are formulated with their drug particles attached to a carrier or as agglomerates in the form of pellets. To facilitate lung deposition, drug particles are de-agglomerated during inhalation. This is achieved by the creation of turbulent energy inside the DPI. The turbulent energy is the product of the patient's inhalation flow multiplied by the DPI's resistance. For this reason, all DPIs that are currently available are classified as passive devices. Increasing the inspiratory flow is generally associated with improved performance for a given device [62].

Different DPIs do not have the same internal resistance to airflow and range from low to high resistance [62, 63]. This resistance means that patients have to inhale deeply and forcefully when using a DPI in order to receive the correct dose. Failure to inhale in this way is another common error when patients use their DPIs [11]. The resistance of a DPI can be classified with respect to the inhalation flow required to produce a pressure drop of 4 kPa. This value was chosen because it is the one recommended by pharmacopoeias for the in vitro characterisation of the dose emitted from a DPI. A device that is characterised as having a low resistance requires an inspiratory flow of >90 L·min⁻¹ to produce this pressure drop. A medium-resistance device requires 60–90 L·min⁻¹. A medium/high-resistance device requires 50–60 L·min⁻¹ and a high-resistance device requires <50 L·min⁻¹ [62, 63]. Table 2 presents the resistances of most DPI devices [62, 63]. Patients will inhale faster through a low-resistance device [63]. However, because the internal energy in a DPI will be the same whether a patient inhales slowly through a DPI with a high resistance, or inhales quickly through a DPI with a low resistance, de-aggregation of the powder will also be the same [63]. For this reason, it is not valid to compare devices or classify them with respect to flow [62, 63]. DPIs with a high resistance tend to produce greater lung deposition than those with a lower resistance [62, 63], but the clinical significance of this is not known. Furthermore, as the inhalation flow increases, deposition in the central airways will increase and distribution uniformity throughout the airways will decrease [17].

Figure 2 shows two possible patient inhalation profiles [64]. Both profiles attain the same peak inhalation flow, but one starts with a fast inhalation (i.e. fast acceleration rate) and the other gradually speeds up its flow (i.e. slow acceleration rate). It has been shown that de-agglomeration of particles takes place inside the device before the metered dose leaves the DPI and is increased if the acceleration is fast at the start of inhalation [65]. Thus, the FPD will be greater and the MMAD smaller when the initial acceleration rate of the inhalation flow is fast [65, 66]. Hence patients should be instructed to inhale forcefully from the beginning of their inhalation.

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Figure 2–

The relationship between dose emission from a dry powder inhaler (DPI) and the patient's inhalation. Reproduced and modified from [64] with permission from the publisher.

Superimposed onto the two inhalation profiles in figure 2 are representations of when the dose is emitted from a capsule DPI and from a reservoir- or blister-type DPI. Clearly, the dose is emitted earlier during inhalation from the reservoir- or blister-type DPI, compared with the capsule DPI. For this reason, inhalation volume becomes important for patients using DPIs with capsules, and patients should repeat the inhalation to ensure that they receive the full dose.

Each DPI has a minimum threshold energy below which de-agglomeration is inefficient, resulting in a reduced emitted dose with a high MMAD and small FPD. Below the minimum threshold energy, the patient will receive no, or very little, therapeutic effect from the drug. For example, it has been shown that the Turbuhaler® provides some clinical effect at low flows [67], but the minimum flow is around 30 L·min⁻¹ and the optimal flow for this device is around 60 L·min⁻¹. The Novolizer® is designed not to release its dose below an inspiratory flow rate of 35 L·min⁻¹ [68]. Another dose cannot be metered until this threshold has been overcome. The Easyhaler® [69] and Clickhaler® [70] have both been shown to be effective at low-inhalation flows. For the Diskus® [71] and Handihaler® [72], the minimum inhalation flow is probably 30 L·min⁻¹. For the Aerolizer®, it is probably >60 L·min⁻¹ [73].

Studies have shown that young (preschool) children with asthma [74] and patients with COPD [75] may have problems achieving minimum flows through some DPIs, and that inhalation flow is reduced during acute exacerbations [76]. No manufacturer has stated the minimum flow for their DPI, although it is clear that this information is needed.

Nebulisers

Nebulisers convert solutions and suspensions into small droplets. Solutions are comprised of drug dissolved in a carrier liquid, whereas suspensions are comprised of solid drug particles suspended in the carrier liquid. An advantage of using nebulisers includes their ability to aerosolise high doses of drugs that are not available with DPIs or pMDIs. In addition, many nebulisers come with facemasks, meaning they can be used by patients <2 yrs old, the elderly and those with severe respiratory distress.

Soft mist inhalers

Currently, there is only one commercially available soft mist inhaler: the Respimat® Soft Mist™ Inhaler. This inhaler is available in Germany for the delivery of the combination of fenoterol and ipratropium bromide (50 and 20 µg per puff, respectively). In Germany, and many other countries, it is available for the delivery of tiotropium bromide, 2.5 µg per puff. The Respimat® Soft Mist™ Inhaler atomises the drug solution using mechanical energy imparted by a spring. When the spring is released, the solution is forced through an extremely fine nozzle system [93, 94]. This produces a fine mist that is slow moving, leading to lower deposition in the mouth and throat and relatively high lung deposition (i.e. ∼39%) [95–97].

Patients with pulmonary arterial hypertenstion

Inhaled iloprost (Ventavis®) is licensed for treatment of PAH with the I-neb® AAD.

HIV-infected (AIDS) or immunocompromised patients

Inhaled pentamidine solution is an anti-infective agent that helps to treat or prevent pneumonia caused by the organism Pneumocystis carinii. The Respirgard II nebuliser is licensed to deliver NebuPent® 300 mg for oral inhalation.

Patients with cystic fibrosis

Patients with CF must inhale one or more therapies at home several times per day. A recent review by Flume et al. [4] examined the clinical evidence for each therapy and provides guidance for the prescription of these therapies. Aerosolised antibiotics have been advocated both for the eradication of the initial infection and for the suppression of the chronic infection due to Pseudomonas aeruginosa in patients with CF. During nebulisation of antibiotics, an expiration filter can be used to prevent contamination of the room and exposure of bystanders to potentially toxic drugs.

Tobramycin inhalation solution is an approved inhaled antibiotic used to treat P. aeruginosa in patients with CF. TOBI® is licensed for inhalation with a PARI LC® Plus nebuliser and a DeVilbiss® Pulmo-Aide® air compressor. Bramitob® is licensed for administration with the PARI LC® Plus and the PARI TURBO Boy® compressor. In the summer of 2011, inhaled tobramycin will be licensed as a dry powder formulation for treatment of CF in some countries. Another inhaled antibiotic, inhaled colistin, is also recommended for treatment of CF. Colistin is recommended to be used with an appropriate jet nebuliser, such as the PARI LC® Plus or the LC® Star, with either the PARI Master® or a similar compressor. Inhaled colistin is also licensed for use with the I-neb® AAD in several countries. Similarly, in some countries, aztreonam inhalation solution is licensed for use with the eFlow® nebuliser as Cayston®.

Nebulised hypertonic saline (7% NaCl) (Hyper-Sal™) has been shown to improve mucociliary clearance in patients with CF [99], and has been tested primarily with the PARI LC® Star nebuliser and PARI Proneb® compressor combination. MucoClear® (6% NaCl) and Hyaneb™ (7% NaCl) are also available for mucociliary clearance. Both manufacturers recommend using a PARI nebuliser for administration.

Recombinant human DNase (rhDNase; dornase alfa) (Pulmozyme®) was developed to degrade free DNA that accumulates within the CF mucus, thereby improving the viscoelastic properties of airway secretions and promoting airway clearance [4]. Recommended nebuliser/compressor combinations for delivering rhDNase include the Hudson T Up-draft II® with Pulmo-Aide®, the Marquest Acorn II® with Pulmo-Aide®, the PARI LC® Jet with PARI Proneb® compressor, the PARI BABY® with PARI Proneb®, and the Durable Sidestream® with Mobilaire® or Porta-Neb®.

A detailed overview of new aerosol delivery devices for treating patients with CF has been written by Kesser and Geller [100].

Pressurised metered-dose inhalers with spacers versus nebulisers to administer short-acting bronchodilators in the emergency room

Until recently, treating asthmatics and patients with COPD in the emergency room usually involved nebulisation of short-acting bronchodilators [1–3, 101, 102]. However, several studies have demonstrated similar efficacy for inhaled bronchodilators using pMDIs with spacers (pMDIs alone are not as effective), compared with nebulisers in emergency rooms in patients with non-life-threatening asthma and in patients with COPD with non-severe exacerbations [103–108]. To more closely match the dose administered by nebulisation, the number of puffs from the pMDI should be increased to between four and 10 puffs in the emergency room setting [104]. Administrations should be repeated as needed [104]. Potential advantages of this approach are cost savings, reduced time of administration and, more importantly, reinforcement of self-management messages.

Nebulisers and patients with severe asthma and chronic obstructive pulmonary disease in the emergency room

Nebulisers are indicated for patients with asthma and COPD who are undergoing severe exacerbations, especially those with alterations of consciousness. Oxygen is commonly employed as the driving gas for jet nebulisers in patients with severe asthma or acute exacerbations of COPD. It is advisable to avoid the uncontrolled use of oxygen in patients with severe COPD because of the risk of hypercapnia with high doses of oxygen [109, 110]. Such patients should be monitored for oxygen saturation and level of consciousness.

Nebulisers and non-cystic fibrosis diseases in hospital

Hypertonic saline (3 or 5%) seems to be the only agent to be clinically effective in bronchiolitis. It has been shown to significantly reduce the length of hospital stay and improve the clinical severity score in infants with acute viral bronchiolitis [111].

Nebulised iloprost (Ventavis®) has been approved in many countries for New York Heart Association class III primary pulmonary hypertension. It is licensed for use with the I-neb® AAD.

Children

Aerosol therapy is often used for the treatment of pulmonary diseases in children. However, many of the paediatric indications are not evidence-based. A recent ERS Task Force guideline discusses recommended treatments for paediatric pulmonary diseases [112].

Many of the new devices also are not approved for use in children, and few studies are available to demonstrate efficacy in this population. However, according to the recently approved EMA guidelines, not all new drug–device combinations need to be tested clinically before approval for use in children is given. New guidelines on the requirements for clinical documentation for orally inhaled products can be found online [113].

The choice of device for children is affected by the child's cognitive ability. Children up to ∼3 yrs of age are generally unable to adopt specific inhalation techniques and are therefore treated with nebulisers with a facemask [89], or with pMDIs with a VHC and facemask [114]. Refer to the inhalation instructions for nebulisers and pMDIs with spacers and facemasks provided in table 4. If the VHC+facemask combination does not achieve a tight fit over the child's nose and mouth, drug delivery to the lungs will be significantly reduced [88]. In a struggling child, it is difficult to achieve a good seal with the facemask and the inhaled dose is substantially reduced. If the child is screaming or crying, most of the inhaled drug deposits in the upper airway, not in the lungs [90].

If a child can be taught to use a mouthpiece, this should be encouraged, since mouthpiece breathing increases lung deposition, compared with facemask breathing [29]. Most (but not all) children can be taught to use a mouthpiece from ∼3 yrs of age. When a child is inhaling through a mouthpiece attached to a nebuliser, place the mouthpiece in the mouth and instruct the child to close their lips around it. The child should then inhale and exhale using normal (tidal) breaths, with occasional deep breaths, until the nebuliser starts to sputter or no more aerosol is produced.

There are different ways to inhale from a pMDI+spacer using a mouthpiece. The easiest technique is inhaling from the spacer with normal, quiet breathing and this is useful when working with young and older children. With appropriate instruction, most children >6 yrs of age should be able to perform a “single-breath” technique with a pMDI+spacer [49]. This technique is described by Roller et al. [49] and appears to improve lung deposition of QVAR®, compared with normal quiet breathing in older children. An experienced individual should instruct the child and caregiver how to perform these techniques and should check to determine whether the child is able to perform it correctly. Refer to the inhalation instructions for spacers with a mouthpiece in table 4. If compliance with a pMDI and spacer is an issue for a child >6 yrs of age, most of these children (but not all) should be able to produce the forceful inhalation that is required to use a DPI [11]. Refer to the inhalation instructions for DPIs in table 4.

In general, a pMDI+spacer is often the cheapest option for aerosol therapy. However, many school-age children will not use the spacer and, therefore, fail to deliver adequate amounts of drug to the lungs. In this context, a DPI may be the best option, although they are not intrinsically “superior” to the pMDI + spacer and are more expensive.

As previously mentioned, nebulisers can be used to deliver aerosols of formulations that cannot be administered as an aerosol with either pMDIs or DPIs. However, the new mesh nebulisers are an expensive option, and cheaper, pneumatic and breath-enhanced devices are more time-consuming and therefore less tolerated than a pMDI+spacer combination that incorporates a facemask in young children.

Several studies have demonstrated similar efficacy for inhaled β₂-adrenergic agonists using pMDIs with spacers (pMDIs alone are not as effective), compared with nebulisers in emergency rooms in children with non-life-threatening asthma [104, 114]. As is the case in adults with asthma, the number of puffs from the pMDI should be increased to between four and 10 puffs in the emergency room setting to more closely match the dose administered by nebulisation [114]. Administrations should be repeated as needed [104].

The elderly

Those prescribing aerosol treatment for the elderly face similar problems to those which are confronted by physicians who treat children. Cognitive decline means that the more complex manoeuvres may be challenging for many elderly patients. The situation is compounded by dexterity issues. Once again, the clinician is obligated to prescribe a delivery system that a patient can and will use effectively. For many with limited abilities to adopt complex inhalation manoeuvres, the simplicity of a jet nebuliser may be a necessary compromise.

Intubated and mechanically ventilated patients

Aerosols can be administered to intubated and mechanically ventilated patients by pMDI and in-line spacer, or by nebuliser. The efficacy of pMDI delivery during mechanical ventilation is dependent on the actuation of the pMDI through a spacer or holding chamber that is tightly inserted into the inspiratory limb side of the ventilator circuit, at ∼15 cm from the endotracheal tube [115, 116]. In adult patients, a tidal volume ≥0.5 L guarantees drug delivery to the lower respiratory tract [117, 118].

The rate of aerosol production and the characteristics of the aerosol generated by a nebuliser differ between devices [119] and depend on ventilator mode [120], pulmonary mechanics [120], inspiratory flow rate [121] and distance from the endotracheal tube [122].

The efficiency of aerosol delivery with both pMDIs and nebulisers is reduced by humidity in the ventilator circuit [123]. In contrast, aerosol delivery is increased with both pMDIs and nebulisers when helium–oxygen mixtures are used in place of air or air–oxygen mixtures to ventilate the patient [124], and both techniques have proven to be clinically effective [125].

Aerosolised albuterol/salbutamol at a dose of 2.5 mg with a nebuliser [126], or four puffs (400 μg) with a pMDI and spacer [116], produces significant bronchodilator effects in mechanically ventilated patients with COPD. Albuterol/salbutamol should be repeated every 3–4 h [115]. Nebulised fenoterol at a dose of 0.4 mg was found to be effective in intubated COPD patients [127]. Both pMDIs and jet nebulisers are equally effective for bronchodilator administration in mechanically ventilated patients, but pMDIs have the advantages of convenience, lower cost and reduced risk of damaging flow sensors.

In mechanically ventilated acute respiratory distress syndrome patients, nebulised prostacyclin and prostaglandin E₁ are as effective as nitric oxide in improving oxygenation and haemodynamics [128, 129].

Newer-generation vibrating mesh nebulisers have been designed specifically for use during mechanical ventilation and have been shown to be efficient for drug delivery in bench studies. These devices are currently under investigation and little clinical information is available.

Patients on noninvasive mechanical ventilation

Aerosols can be administered to patients receiving noninvasive mechanical ventilation (NIMV) by pMDI and spacer with facemask, or by nebuliser with facemask. Based on the currently available literature [130], the recommended technique for using a pMDI in patients receiving NIMV is to: 1) minimise leaks in the mask and/or circuit; 2) place a cylindrical spacer (volume ∼140 mL) between the circuit and mask; 3) shake the pMDI canister well and place it in the adapter of the spacer chamber; 4) actuate pMDI at the beginning of inspiratory airflow from the ventilator; 5) repeat actuations after an interval of ≥15 s; and 6) monitor the patient and assess the clinical response. The recommended technique for nebulisers is to: 1) minimise leaks in the mask and or circuit; 2) fill the nebuliser with drug solution up to optimal fill volume (4–6 mL); 3) place the nebuliser in an upright position between the circuit and mask; 4) operate the nebuliser with a gas flow of 6–8 L·min⁻¹; 5) tap the nebuliser periodically until it begins to sputter or stops producing aerosol; 6) remove the nebuliser from the circuit, rinse with sterile water, air dry and store in a clean space; and 7) monitor the patient and document clinical response.

The position of the leak port in the circuit influences the efficiency of drug delivery from a nebuliser during noninvasive ventilation, but it does not influence the efficiency of drug delivery from pMDIs [131]. Nebuliser efficiency is higher with the leak port in the circuit, as compared with a leak port in the facemask [132]. Furthermore, the findings of Calvert et al. [132] suggest that a nebuliser placed between the ventilator and leak port (ventilator, nebuliser, leak port, facemask) performs with higher efficiency than placement of the nebuliser between the leak port (ventilator, leak port, nebuliser, facemask).